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Impaired interactions between mouse Eyal harboring mutations found in patients with branchio-oto-renal syndrome and Six, Dach, and G proteins.

Abstract
Mutations in the EYA1 gene are responsible for branchio-oto-renal (BOR) syndrome as well as for other ocular defects. Most of the mutations are located within or in the vicinity of the EYA domain, which is highly conserved in the EYA protein family. The EYA domain is required for protein-protein interactions, which are important to the biological function of EYA proteins. To determine how EYA1 mutations cause BOR syndrome and/or ocular defects, we tested the effects of Eya1 mutations on interactions with Six. Dach, and G proteins by mammalian two-hybrid and GST-pulldown assays. Defective interactions were noted between BOR-type mutations S486P and L504R of Eya1 and Dach1, G proteins, and some Six proteins. These mutations impaired the activation of transcription from a Six-responsive gene, myogenin, with Six5. S486P and L504R showed an altered digestion pattern with trypsin, and L504R also decreased the sensitivity to V8 protease digestion and produced a peptide fragment with a different M(r). Our results suggest that defective protein-protein interactions of the mutations in the EYA domain underlie BOR syndrome and that SIX, DACH, and/or G proteins are possibly involved in the pathogenic processes.
AuthorsHidenori Ozaki, Yoko Watanabe, Keiko Ikeda, Kiyoshi Kawakami
JournalJournal of human genetics (J Hum Genet) Vol. 47 Issue 3 Pg. 107-16 ( 2002) ISSN: 1434-5161 [Print] England
PMID11950062 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Drosophila Proteins
  • Intracellular Signaling Peptides and Proteins
  • MYOG protein, human
  • Myog protein, mouse
  • Myogenin
  • Nuclear Proteins
  • Trans-Activators
  • dac protein, Drosophila
  • EYA1 protein, human
  • Eya1 protein, mouse
  • Protein Tyrosine Phosphatases
  • Endopeptidases
  • GTP-Binding Proteins
Topics
  • Amino Acid Substitution
  • Animals
  • Branchio-Oto-Renal Syndrome (genetics, physiopathology)
  • DNA Mutational Analysis
  • Drosophila Proteins
  • Endopeptidases
  • GTP-Binding Proteins (genetics, physiology)
  • Gene Expression Regulation
  • Genes, Reporter
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mutation
  • Myogenin (physiology)
  • Nuclear Proteins (genetics, physiology)
  • Protein Structure, Tertiary (genetics, physiology)
  • Protein Tyrosine Phosphatases
  • Trans-Activators (genetics, physiology)
  • Two-Hybrid System Techniques

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